Article

Serine 776 of Ataxin-1 Is Critical for Polyglutamine-Induced Disease in SCA1 Transgenic Mice

Department of Laboratory Medicine and Pathology, University of Minnesota, Mayo Mail Code 206, Minneapolis, MN 55455, USA.
Neuron (Impact Factor: 15.98). 06/2003; 38(3):375-87. DOI: 10.1016/S0896-6273(03)00258-7
Source: PubMed

ABSTRACT Polyglutamine-induced neurodegeneration in transgenic mice carrying the spinocerebellar ataxia type 1 (SCA1) gene is modulated by subcellular distribution of ataxin-1 and by components of the protein folding/degradation machinery. Since phosphorylation is a prominent mechanism by which these processes are regulated, we examined phosphorylation of ataxin-1 and found that serine 776 (S776) was phosphorylated. Residue 776 appeared to affect cellular deposition of ataxin-1[82Q] in that ataxin-1[82Q]-A776 failed to form nuclear inclusions in tissue culture cells. The importance of S776 for polyglutamine-induced pathogenesis was examined by generating ataxin-1[82Q]-A776 transgenic mice. These mice expressed ataxin-1[82Q]-A776 within Purkinje cell nuclei, yet the ability of ataxin-1[82Q]-A776 to induce disease was substantially reduced. These studies demonstrate that polyglutamine tract expansion and localization of ataxin-1 to the nucleus of Purkinje cells are not sufficient to induce disease. We suggest that S776 of ataxin-1 also has a critical role in SCA1 pathogenesis.

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Available from: Tao Zu, Aug 27, 2015
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    • "We first established that these cells do form oligomers (Figure 3—figure supplement 1). As a negative control, we used cells that express mRFP-ATXN1(82Q,S776A), a mutant form of ATXN1 that cannot be phosphorylated at Ser776 and is not toxic (Emamian et al., 2003; Jorgensen et al., 2009; Park et al., 2013). The anti-oligomer antibody detected the smaller inclusion bodies (350–900 nm) but did not recognize the larger inclusions (>900 nm), suggesting that these larger inclusions are more complex and composed of higher order aggregates, likely to be fibrillar in nature. "
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    ABSTRACT: Recent studies indicate that soluble oligomers drive pathogenesis in several neurodegenerative proteinopathies, including Alzheimer and Parkinson disease. Curiously, the same conformational antibody recognizes different disease-related oligomers, despite the variations in clinical presentation and brain regions affected, suggesting that the oligomer structure might be responsible for toxicity. We investigated whether polyglutamine-expanded Ataxin1, the protein that underlies spinocerebellar ataxia type 1, forms toxic oligomers and, if so, what underlies their toxicity. We found that mutant ATXN1 does form oligomers and that oligomer levels correlate with disease progression in the Atxn1(154Q/+) mice. Moreover, oligomeric toxicity, stabilization and seeding require interaction with Capicua, which is expressed at greater ratios with respect to ATXN1 in the cerebellum than in less vulnerable brain regions. Thus, specific interactors, not merely oligomeric structure, drive pathogenesis and contribute to regional vulnerability. Identifying interactors that stabilize toxic oligomeric complexes could answer longstanding questions about the pathogenesis of other proteinopathies.
    eLife Sciences 05/2015; 4. DOI:10.7554/eLife.07558 · 8.52 Impact Factor
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    • "Other polyglutamine proteins have RXRXXS motifs. Phosphorylation of polyglutamine-expanded huntingtin at serine 421 by Akt has been shown to be protective in striatal neurons (Humbert et al., 2002), whereas phosphorylation of polyglutamine-expanded ataxin-1 at serine 776 enhances toxicity (Emamian et al., 2003). Our findings indicate the existence of an additional important level of regulation of phosphorylation at the RXRXXS motif by arginine methylation, which may also play a critical role in polyglutamine diseases other than SBMA. "
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    Neuron 01/2015; 85(1):88-100. DOI:10.1016/j.neuron.2014.12.031 · 15.98 Impact Factor
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    • "reflects that the interaction of ATXN1 and RBM17 requires the phosphorylation of this Ser776 pATXN1 residue [15]. Compared with the interactions of ULM5 peptide bound in RBM17, pATXN1 peptide makes additional strong H-bonding network with RBM17 using Arg773 pATXN1 residue. "
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    ABSTRACT: Spinocerebellar Ataxia Type1 (SCA1) is a dominantly inherited neurodegenerative disease and belongs to polyglutamine expansion disorders. The polyglutamine expansion in Ataxin-1 (ATXN1) is responsible for SCA1 pathology. ATXN1 forms at least two distinct complexes with Capicua (CIC) or RNA-binding motif protein 17 (RBM17). The wild-type ATXN1 dominantly forms a complex with CIC and the polyglutamine expanded form of ATXN1 favors to form a complex with RBM17. The phosphorylation of Ser776 in ATXN1 is critical for SCA1 pathology and serves as a binding platform for RBM17. However, the molecular basis of the phospho-specific binging of ATXN1 to RBM17 is not delineated. Here, we present the modeled structure of RBM17 bound to the phosphorylated ATXN1 peptide. The structure reveals the phosphorylation specific interaction between ATXN1 and RBM17 through a salt-bridge network. Furthermore, the modeled structure and the interactions between RBM17 and ATXN1 were validated through mutagenesis study followed by Surface Plasmon Resonance binding experiments. This work delineates the molecular basis of the interaction between RBM17 and the phosphorylated form of ATXN1, which is critical for SCA1 pathology. Furthermore, the structure of RBM17 and pATXN1 peptide might be utilized to target RBM17-pATXN1 interaction to modulate SCA1 pathogenesis.
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